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European Heart Journal Advance Access originally published online on October 22, 2007
European Heart Journal 2008 29(10):1250-1258; doi:10.1093/eurheartj/ehm442
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org

DNA variants, plasma levels and variability of C-reactive protein in myocardial infarction survivors: results from the AIRGENE study

Melanie Kolz1, Wolfgang Koenig2,*, Martina Müller1,3, Mariarita Andreani4, Sonja Greven5, Thomas Illig1, Natalie Khuseyinova2, Demosthenes Panagiotakos6, Göran Pershagen7, Veikko Salomaa8, Jordi Sunyer9, Annette Peters for the AIRGENE Study Group1

1 GSF National Research Center for Environment and Health, Institute of Epidemiology, Neuherberg, Germany
2 Department of Internal Medicine II—Cardiology, University of Ulm Medical Centre, Robert-Koch Strasse 8, D-89081 Ulm, Germany
3 Institute of Medical Information Processing, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany
4 Catholic University, Rome, Italy
5 Department of Statistics, Ludwig-Maximilians-Universität, Munich, Germany
6 Department of Hygiene and Epidemiology, University of Athens Medical School, Athens, Greece
7 Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden
8 Department of Epidemiology and Health Promotion, National Public Health Institute (KTL), Helsinki, Finland
9 Environmental Epidemiology Research Centre (CREAL), Institute Municipal Investigació Mèdica (IMIM), Barcelona, Spain

Received 21 February 2007; revised 7 September 2007; accepted 13 September 2007; online publish-ahead-of-print 22 October 2007.

* Corresponding author. Tel: +49 731 500 45001, Fax: +49 731 500 45021. Email: wolfgang.koenig{at}uniklinik-ulm.de


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Conclusions
 Funding
 Acknowledgement
 References
 
Aims: C-reactive protein represents the classical acute-phase protein produced in the liver in response to inflammatory stimuli. This study evaluated the association of gene polymorphisms with differences in C-reactive protein concentrations and assessed its intra-individual variability as a marker of individual response.

Methods and results: One thousand and three myocardial infarction (MI) survivors were recruited in six European cities, and C-reactive protein concentrations were measured repeatedly during a 6-month period. We investigated 114 polymorphisms in 13 genes, all involved in the innate inflammatory pathway. We found two polymorphisms within the C-reactive protein (CRP) gene rs1800947 and rs1205, of which the minor alleles were strongly associated with lower levels of C-reactive protein (P < 10–6). A haplotype, identified by those two polymorphisms, was associated with the lowest C-reactive protein concentrations (P < 10–6). Additionally, the minor alleles of several variants were significantly associated with greater individual variability of C-reactive protein concentrations (P < 10–3).

Conclusion: The present study investigated the association of polymorphisms with inter- and intra-individual variability of C-reactive protein levels. Two minor alleles of C-reactive protein variants were associated with lower C-reactive protein concentrations. Regarding intra-individual variability, we observed associations with the minor alleles of several variants in selected candidate genes, including the CRP gene itself.

Key Words: Epidemiology • Inflammation • Genetics • C-reactive protein • Myocardial infarction


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Conclusions
 Funding
 Acknowledgement
 References
 
C-reactive protein, a member of the pentraxin family, is synthesized in the liver upon stimulation by various inflammatory cytokines and hormones. Levels of C-reactive protein may increase by as much as 1000-fold from usual concentrations of <1 mg/L during the acute phase of infection or injury response. Following an inflammatory stimulus, C-reactive protein concentrations rise after 6 h and peak at ~48 h. The half-life of C-reactive protein in plasma is 19 h; therefore, the main determinant of the plasma concentration is the synthesis rate, reflecting the inflammatory stimulus.1

Research over the last 15 years has provided convincing evidence that atherosclerosis has typical features of an inflammatory disease. There is unequivocal evidence for a local inflammation in the artery wall which is accompanied by a systemic low-grade inflammatory response. Such response can be measured by a variety of inflammatory biomarkers. The largest database so far has been accumulated for C-reactive protein. More than 25 prospective studies have shown a strong and consistent association between elevated C-reactive protein concentrations and various cardiovascular endpoints.2 In addition, evidence from in vitro and clinical studies suggest that C-reactive protein might also be implicated in the pathophysiology of atherogenesis, which, however, still represents a controversial issue.

C-reactive protein concentrations are determined by several factors, including age and body mass index (BMI).3 There is also evidence for a strong genetic component, with heritability estimates of 35–40%.1 In addition, several studies reported associations between single nucleotide polymorphisms (SNPs) in the CRP gene or other genes involved in the inflammatory pathway and the inter-individual variability of C-reactive protein levels, but the results are conflicting.3–14 Since a chronic low-grade inflammation may be related to common genetic predisposition and environmental risk factors, the modulation of the systemic immune balance through gene polymorphisms might play a crucial role.

Therefore, the present study sought to investigate the association between genetic variants involved in the inflammatory pathway with differences in C-reactive protein concentrations in a high-risk group of patients with a history of (MI). In addition, the use of repeated measurements enabled us not only to assess differences in mean C-reactive protein concentrations but also to determine the genetic component of its within-subject variability as a marker of the individual response.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Conclusions
 Funding
 Acknowledgement
 References
 
Study population
The present multicentre longitudinal study ‘Air Pollution and Inflammatory Response in Myocardial Infarction Survivors: Gene–Environment Interaction in a High Risk Group’ (AIRGENE) was conducted between May 2003 and July 2004 in six European cities: Athens, Rome, Barcelona, Augsburg, Stockholm, and Helsinki. A total of 1003 participants, who survived an MI between 3 months and 6 years before entry into the study, were recruited and for each subject six repeated clinical visits including blood draws were scheduled every 4–6 weeks. A detailed study protocol including the selection of participants has been reported elsewhere.15

The study complies with the declaration of Helsinki. Approval was obtained from the Local Ethics Committees and all patients gave their informed consent. The health status of each patient was assessed at the first visit. Clinical examinations included the measurement of blood pressure (BP) and the determination of the BMI (kg/m2). Furthermore, all patients were subjected to a standardized questionnaire asking about medication, sociodemographic characteristics, lifestyle habits, history of coronary heart diseases, and other co-morbidities.

Laboratory methods
C-reactive protein was determined by an immunonephelometric method (Dade Behring N Latex High Sensitivity CRPTM mono assay) on a Behring Nephelometer II analyzer. The detection limit was 0.16 mg/L, and the measurement range was 0.175–1100 mg/L, according to manufacturer's instruction. Coefficients of variation (CV) were between 3.5 and 8.0% for a C-reactive protein concentration of 2.4 mg/L and between 3.2 and 5.8% for a C-reactive protein concentration of 13.5 mg/L. To control for the reliability of the laboratory tests, blind duplicates were sampled from every 30th patient. The CV for the original compared with the duplicate samples ranged from 1.5 in Barcelona to 4.1 in Stockholm. Overall, 5813 C-reactive protein plasma samples were collected. The average number of repeated visits per study subject ranged from 4.5 in Athens to 6.6 in Barcelona. Total cholesterol, N-terminal proB-type natriuretic peptide (NT-proBNP) and glycosylated haemoglobin (HbA1c) were measured by routine methods.

Selection and genotyping of polymorphisms
Genotyping analyses were carried out by means of matrix-assisted laser desorption ionization-time of flight analysis of allele-dependent primer extension products as described elsewhere.16 Altogether 114 polymorphisms were successfully genotyped with an average success rate of 99.06%. To control for reproducibility of genotyping data, 30% of randomly selected samples were genotyped in duplicate. The discrepancy rate was 0.18%. Each SNP was tested for departures from Hardy–Weinberg equilibrium (HWE) by means of a {chi}2 test or Fisher's exact test depending on allele frequency for all cities combined. Seventeen SNPs showed deviations from HWE. They were not excluded from further analysis, because our study is not a random population sample, but a highly selected group of MI survivors. For detailed description of the selected SNPs including frequencies and HWE statistics please, see Supplementary material online, Table S1.

Statistical analysis
Data were analysed using mixed effects models with random patient effects to account for the clustered data structure (SAS Proc MIXED). To model correlations between the repeated measures in each patient, we assumed compound symmetry structure for the covariance matrix. This assumption was verified in a model assuming an exponentially decaying correlation with time in the errors, showing that the estimated correlation between two measurements was 0.64 for two visits 4 weeks apart compared with 0.62 for two visits 20 weeks apart. C-reactive protein needed to be log-transformed to fulfill the model assumption of residual normality. Confounder models were built identifying the time-invariant patient characteristics associated with average levels of C-reactive protein to allow the assumption of a normally distributed random patient intercept. All analyses were done crude and with a multivariable-adjusted model including city, sex, BMI, age, packyears of smoking, systolic BP, total cholesterol, number of previous MI, health status, HbA1c, NT-proBNP (log-transformed), chronic obstructive pulmonary disease, chronic bronchitis, lipid-lowering medication, and hypertension. SNPs were analysed separately. To assess differences in intra-individual variability, mean and variance were then modelled simultaneously allowing for different error variances between genotype groups. Homogeneity of variances was tested using the asymptotic {chi}2 distribution of the restricted likelihood ratio test statistic, comparing the two models with equal and unequal variances. For heterogeneous variances, results for the association with the mean were reported from the appropriate model. Finally, a sensitivity analysis was performed, excluding outlying subject variances according to Cochran's test, and outlying patient mean values using Reed's criterion.17 Partial r2 was analysed with SAS Proc REG using the mean C-reactive protein concentrations of each patient.

Haplotype reconstruction was performed using the expectation–maximization algorithm haplo.em,18 as it is available within the R software library haplo.stats. To avoid large reconstruction errors resulting from missing data, haplotype estimation is based only on patients with complete genotype information. In order to avoid bias resulting from population stratification, haplotype probabilities were estimated for each centre separately. Haplotypes with frequencies <5% in all centres were collected into a separate group of rare haplotypes (‘haplo rare’). For the description of haplotypes, we used the nomenclature introduced by Carlson et al.19

The global significance level of 5% was corrected for the number of independent tests following the Bonferroni procedure [0.05/(64 x 2) = 0.0004] to minimize the conservativeness by removing redundant SNPs. The number of independent tests was calculated as the number of effective loci obtained through spectral decomposition of the correlation matrix of all SNPs analysed.20 All analyses unless otherwise noted were performed using the statistical package SAS Version 9.1.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Conclusions
 Funding
 Acknowledgement
 References
 
Baseline characteristics of the study population
Table 1 shows the baseline characteristics of the study participants. More patients participated in the Northern and Central European countries. Only in Helsinki, Stockholm, and Augsburg was it possible to avoid recruiting regular smokers. Also, a history of smoking was more prevalent in the Southern European centres. The highest C-reactive protein concentrations were found in Barcelona with a geometric mean concentration of 2.03 mg/L, whereas the lowest were observed in Helsinki and Augsburg (1.18 mg/L). Detailed data on C-reactive protein concentrations in all centres are presented in the Supplementary material online, Table S2.


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  		Table 1 Study description

 
Association of CRP polymorphisms with C-reactive protein concentrations using repeated measurements
Seven SNPs were successfully genotyped in the CRP gene. The characteristics of these SNPs are summarized in Table 2. Frequencies did not differ between cities except for rs1205 (P < 0.05). For two SNPs (rs1800947 and rs3093068), the homozygotes for the minor allele were pooled with the heterozygotes in order to avoid conclusions from low numbers. The triallelic rs3091244 was analysed assuming a dose-dependent effect for the major allele as shown in previous studies3 and numbers were too low for unconstrained modelling.


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  		Table 2 Description of CRP variants. The nucleotide position is given relative to the ATG start codon

 
One highly preserved linkage disequilibrium (LD) block covering the whole gene was observed with D' > 0.95. High correlations were detected between rs1417938, rs1130864, and the A allele of rs3091244 (r2 > 0.99). The T allele of the rs3091244 was additionally correlated with the C allele of the rs3093068 (r2 > 0.84).

The results of the SNP association analysis with C-reactive protein plasma concentrations are summarized in Table 3. To correct for multiple testing, the significance level was reduced to {alpha} = 0.0004, corresponding to an overall significance level of {alpha} = 0.05. Two SNPs (rs1800947 and rs1205) were significantly associated with lower C-reactive protein concentrations. Figure 1 shows the results of those two SNPs stratified by city, although the heterogeneity between the stratified estimates was not statistically significant (P > 0.1). Coefficients for the clinical covariates revealed that higher BMI was associated with higher concentrations of C-reactive protein (P < 10–23). Concentrations of total cholesterol (P < 10–5) and NT-proBNP (P < 10–5) had a similar effect, although the correlation was weaker. Additionally, smoking was significantly associated with C-reactive protein (P < 10–5). None of the SNP x covariate interaction terms tested turned out to be significant. Covariates and CRP polymorphisms explained 27% of the inter-individual variability in C-reactive protein concentrations. BMI explained the biggest proportion (11%), followed by smoking (3%). rs1205, rs1800947, total cholesterol, and NT-proBNP each explained 2%, whereas all other covariates contributed <1%.


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  		Table 3 Association analysis of seven SNPs in the CRP gene with plasma concentrations, given as the geometric mean and the appropriate geometric standard deviation in brackets

 

Figure 1
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  		Figure 1 Association results stratified by city for rs1205 and rs1800947. The % change of the geometric mean of C-reactive protein is given together with 95% confidence intervals for the minor allele vs. the major allele and for the heterozygotes vs. the major allele. For rs1800947, the minor allele homozygotes and heterozygotes were pooled due to low numbers

 
Association of CRP haplotypes with C-reactive protein concentrations using repeated measurements
Haplotype reconstruction showed that only for two patients the best-guess haplotype probabilities ranged between 80 and 90%, whereas all other best-guess haplotype pairs occurred with probabilities >95%. This indicates that no substantial loss is expected due to the modelling of best-guess haplotypes only. Because of the nearly complete correlation with rs1417938, rs1130864 was excluded from haplotype reconstruction.

Haplotypes showed a homogeneous distribution across European cities, except for Helsinki. More detailed information about the distribution of haplotypes across centres is shown in Supplementary material online, Table S3. Three major haplotypes were observed with frequencies ranging from 26.2 to 32.2%. The haplotype H3, carrying the major allele at all loci, had a frequency of 1.2% and was thus pooled into the group haplo rare. The most common haplotype was used as the reference category. Results of the association analysis with CRP haplotypes are shown in Table 4. H1, the haplotype containing the minor alleles of both rs1205 and rs1800947, was significantly associated with lower C-reactive protein concentrations (P < 10–6).


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  		Table 4 Association analysis of CRP haplotypes with C-reactive protein plasma concentrations

 
Association of single nucleotide polymorphisms involved in the inflammatory pathway with C-reactive protein concentrations
One hundred and seven polymorphisms were genotyped in selected candidate genes involved in the regulation of the innate inflammatory pathway. Selected candidate genes were interleukin-6 (IL6), fibrinogen (FG{alpha}, FGβ, and FG{gamma}), tumor necrosis factor-alpha (TNF{alpha}), lymphotoxin-alpha (LTA), interleukin-18 (IL18), toll-like receptor 4 (TLR4), interleukin-10 (IL10) and three components of the NF{kappa}B complex (NF{kappa}B1, NF{kappa}BIA and RELA). None of these polymorphisms involved in the inflammatory pathway was associated with significant differences in C-reactive protein concentrations after correction for multiple testing (data not shown).

Analysis of intra-individual variability
Substantial within-subject variability of C-reactive protein concentrations was observed for all centres. The proportion of subjects with C-reactive protein concentrations always above 3 mg/L varied between cities (6% in Athens, 14% Barcelona, 10% Rome, 7% Augsburg, 7% Helsinki, and 11% Stockholm). Similarly, the proportion with C-reactive protein concentrations which varied between below and above 3 mg/L differed between centres (40% in Athens, 52% Barcelona, 38% Rome, 39% Augsburg, 32% Helsinki, and 38% Stockholm). We investigated whether differences in the variability within an individual as a marker of the individual response was influenced by genetic polymorphisms. Several SNPs were significantly associated with intra-individual variability after correction for multiple testing. Results are summarized in Table 5. In addition to rs1417938 and rs1130864 in the CRP gene, rs2070006 and rs2070011 in the FG{alpha} gene, and rs1800890 and rs6676671 in the IL10 gene were highly correlated (r2 > 0.95). However, after excluding outlying subject variances and outlying patient mean values in sensitivity analysis, rs361525 (TNF{alpha}), rs2070016 (FG{alpha}), rs3774964 (NFKB1), and the correlated rs1800890 and rs6676671 in the IL10 gene failed to obtain statistical significance.


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  		Table 5 Significant results of the analysis of intra-individual variability

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Conclusions
 Funding
 Acknowledgement
 References
 
CRP polymorphisms and C-reactive protein plasma concentrations
We investigated seven SNPs within the CRP gene in 1003 MI survivors and found two SNPs, rs1800947 and rs1205, where the minor alleles were strongly associated with lower concentrations of C-reactive protein. Each SNP explained 2% of the variance. The effect remained stable after multivariable adjustment. These results are consistent with some5–9,12,14 but not all previous studies.4 A recently published study found the minor alleles of those two SNPs being significantly associated with decreased risk of cardiovascular disease mortality.21 rs1800947, described as 1059 G/C polymorphism in exon 2 (L184L), is located in a segment with evolutionary conservation which suggests functional importance of this region. Stratification by city as described in Figure 1 showed that the effect for the minor allele of rs1800947 seemed to be stronger in Northern and Central Europe. However, differences between centres seen in stratified analysis were not statistically significant for both SNPs. As shown in Table 3, rs1205 demonstrated a dose-dependent effect, with each copy of the minor allele increasing the difference in C-reactive protein concentrations. rs1205 is located in the 3' flanking region or the 3'-UTR, depending on the transcript, a region possibly controlling RNA cleavage, stability, export, and intracellular localization. The frequency of the rs1205 tends to differ between populations. Using the HapMap Catalogue, frequencies of the minor allele of this SNP ranged from 0.15 to 0.73% in different populations. In our European sample, we observed a frequency for the minor allele ranging from 5% in Barcelona to 15% in Helsinki (P < 0.05).

Recently published studies found a probably functional triallelic SNP (rs3091244) in the promoter of the CRP gene associated with C-reactive protein plasma concentrations.3 We could not replicate this finding after correction for multiple testing, possibly due to our selected population of MI survivors.

CRP haplotypes and plasma concentrations of C-reactive protein
The strength of LD within the CRP gene was reflected by restricted haplotype diversity. We observed five haplotypes with a frequency >5%. Similar to the association results of the single SNPs, we found haplotype H1, tagged by SNPs rs1205 and rs1800947, associated with the lowest plasma concentrations of C-reactive protein. This is consistent with the result of a recently published Mendelian randomization study.12 Additionally, a population-based study showed that this haplotype was associated with the lowest concentrations of C-reactive protein.8 Three other studies also found H1 and H2 being significantly associated with lower C-reactive protein concentrations; however, after correction for multiple testing, we could not replicate the significant result for H2.7,9,10

Polymorphisms involved in the inflammatory pathways and C-reactive protein concentrations
Even after accounting for known environmental and genetic factors, much of the variation in C-reactive protein levels has yet to be explained. Therefore, other polymorphisms in other genes might be associated with C-reactive protein levels and may account for the observed heritability.

Previously, several studies reported on associations of C-reactive protein concentrations with polymorphisms in genes for IL6,13 LTA,11 and TNF{alpha}.4 We analysed 107 polymorphisms in selected candidate genes, all involved in the regulation of the immune system. None of these polymorphisms was associated with significant differences in C-reactive protein concentrations after correction for multiple testing. Similarly, a recently published study investigated polymorphisms in nine innate immunity genes, including TLR4 and NFKB1, without detecting differences in C-reactive protein concentrations.22

Although we found no contribution of these polymorphisms to the inter-individual variation in C-reactive protein concentrations, other polymorphisms or variation in other genes involved in the inflammatory cascade may be associated with differences in C-reactive protein concentrations.

Intra-individual variability of C-reactive protein concentrations
Within-person variability for C-reactive protein was high in the repeated visits, even in cities that indicated very low variability in blind duplicate samples. We investigated whether polymorphisms influence this intra-individual variability, a marker of the individual response. External stimuli might lead to a short-term increase in C-reactive protein concentrations in subjects carrying the inducible genotype, but within the range of overall population variability. Therefore, the overall distribution of C-reactive protein values measured would not be changed and subjects without this genotype would display the same overall mean. An SNP in a candidate gene not associated with C-reactive protein levels might be associated with intra-individual variability of C-reactive protein, since this implies a short-term effect which could be rapidly compensated.

The minor alleles of several variants in selected candidate genes were significantly associated with either greater or smaller individual variability of C-reactive protein concentrations even after excluding outlying observations. However, other studies are essential to confirm this association.

Study limitations and strengths
Participants of the AIRGENE study represent a highly selected group of MI survivors and thus are not representative for the general population. The majority of patients were treated with lipid-lowering compounds, mainly statins, which are associated with reduced plasma C-reactive protein concentrations.23 However, detailed adjustment for medication and clinical covariates has been performed. Population stratification can also be a confounding factor in genetic association studies. Therefore, main results were analysed, stratified by centre, and tested for heterogeneity. The repeated measurements represent a major advantage of the present study, particularly because of the high intra-individual variability. A recent paper on the effect of single measurements in the studies of biomarkers has shown that for C-reactive protein using only a single measurement could modify the regression coefficient by 40%.24


   Conclusions
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
Funding
 Acknowledgement
 References
 
The present study investigated the association of DNA variants with inter- and intra-individual variability of C-reactive protein. The minor alleles of two variants in the CRP gene were associated with lower C-reactive protein concentrations. Regarding intra-individual variability, we observed associations with the minor alleles of several variants in selected candidate genes, including the CRP gene itself.


   Funding
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Funding
Acknowledgement
 References
 
Parts of this work were supported by grants from the German Ministry of Education and Research (BMBF)/National Genome Research Network (NGFN). The authors are indebted to the AIRGENE study group.


   Acknowledgement
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Funding
 Acknowledgement
References
 
The AIRGENE study was funded as part of the European Union's 5th Framework Programme, key action number 4: ‘Environment and Health’, contract number QLRT-2002-02236.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Conclusions
 Funding
 Acknowledgement
 References
 

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 Nicotine Tob ResHome page
J. Sunyer, F. Forastiere, J. Pekkanen, E. Plana, M. Kolz, R. Pistelli, B. Jacquemin, I. Bruske-Hohlfeld, Ch. Pitsavos, T. Bellander, et al.
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